Method for producing 2,2-difluoroethylamine derivatives by imine hydrogenation

ABSTRACT

Process for preparing 2,2-difluoroethylamine derivatives, wherein compounds of the general formula (IV) are hydrogenated to the corresponding 2,2-difluoroethylamine derivatives of the general formula (III), where the A radical is as defined in the description:

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a §371 National Stage Application of PCT/EP2008/007272 filed Sep. 5, 2008, which claims priority to European Application 07116641.7 filed Sep. 18, 2007.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for preparing 2,2-difluoroethanamine derivatives proceeding from 2,2-difluoroethylimine derivatives. The present invention further provides the 2,2-difluoroethylimine derivatives used as starting compounds in this process according to the invention, the preparation thereof and the use thereof for preparing 2,2-difluoroethylamine derivatives.

2. Description of Related Art

Derivatives of 2,2-difluoroethylamines are important intermediates for preparing active agrochemical ingredients. Appropriate 2,2-difluoroethylamine derivatives can be used, for example, as insecticidally active enaminocarbonyl compounds, for example of 4-aminobut-2-enolide compounds. Enaminocarbonyl compounds which contain 2,2-difluoroethylamino units are known, for example, from WO 2007/115644 and WO 2007/115646.

WO 2007/115644 discloses that 2,2-difluoroethylamine derivatives, for example the compound of the formula (Ma) below, can be prepared by alkylating the amine of the formula (Ia) with optionally substituted chloromethylpyridine of the formula (IIa) (scheme 1 of DE 10 2006 015 467 A; cf. preparation of starting compounds; compounds of the formula (III); N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethyl-1-amine).

A disadvantage in this process is the low yield of 53%, which is caused by the possible polyalkylation of the nitrogen atom. This proportion of polyalkylation can only be reduced through the use of a large excess of amine, which is, though, uneconomic in the case of a costly amine.

SUMMARY OF THE INVENTION

Proceeding from this prior art, it is an object of the present invention to provide a process for preparing 2,2-difluoroethylamine derivatives, which is preferably simple and inexpensive to perform. The 2,2-difluoroethylamine derivatives obtainable by this desired process should preferably be obtained with high yield and high purity. More particularly, the desired process should enable the desired target compounds to be obtained without the need for complex purification methods.

This object is achieved by a process for preparing 2,2-difluoroethylamine derivatives.

The process according to the invention is characterized in that 2,2-difluoroethylimine derivatives of the general formula (IV) are hydrogenated to the corresponding target compounds of the general formula (III) according to the following scheme 2:

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

The invention thus envisages that the desired 2,2-difluoroethylamine derivatives of the general formula (III) are prepared by a hydrogenation of the corresponding 2,2-difluoroethylimine derivatives of the general formula (IV). The desired 2,2-difluoroethylamine derivatives of the general formula (III) are obtained under the inventive reaction conditions and preferred reaction conditions specified in detail below with good yields in high purity, as a result of which the process according to the invention overcomes the abovementioned disadvantages. The desired compounds are obtained in a purity which generally does not necessitate an extensive workup of the direct reaction product. Compared to the process known from the prior art, which proceeds from an amine to be alkylated according to scheme 1, the yields can be improved by the process according to the invention. Furthermore, the purity achieved of the desired target compound by the process according to the invention is greater, since no polyalkylation takes place.

In the context of the present invention, a derivative refers to a similar structure derived from the organic base structure (unit) in question, i.e. a 2,2-difluoroethylamine derivative is understood to mean, for example, a compound which includes a 2,2-difluoroethylamine unit.

In the abovementioned general formulae (III) and (IV), the A radical is defined as follows:

-   -   pyrid-2-yl or pyrid-4-yl, or pyrid-3-yl which is optionally         6-substituted by fluorine, chlorine, bromine, methyl,         trifluoromethyl or trifluoromethoxy, or pyridazin-3-yl which is         optionally 6-substituted by chlorine or methyl, or pyrazin-3-yl,         or 2-chloropyrazin-5-yl, or 1,3-thiazol-5-yl which is optionally         2-substituted by chlorine or methyl, or     -   pyrimidinyl, pyrazolyl, thiophenyl, oxazolyl, isoxazolyl,         1,2,4-oxadiazolyl, isothiazolyl, 1,2,4-triazolyl or         1,2,5-thiadiazolyl, which is optionally substituted by fluorine,         chlorine, bromine, cyano, nitro, C₁-C₄-alkyl (which is         optionally substituted by fluorine and/or chlorine),         C₁-C₃-alkylthio (which is optionally substituted by fluorine         and/or chlorine), or C₁-C₃-alkylsulphonyl (which is optionally         substituted by fluorine and/or chlorine), or

-   -   in which     -   X is halogen, alkyl or haloalkyl and     -   Y is halogen, alkyl, haloalkyl, haloalkoxy, azido or cyano.

Preferred, particularly preferred and very particularly preferred definitions of the A radical shown in the abovementioned general formulae (III) and (IV) are elucidated below.

-   A is preferably selected from the group consisting of     6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid-3-yl,     6-methylpyrid-3-yl, 6-trifluoromethylpyrid-3-yl,     6-trifluoromethoxypyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl,     6-methyl-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl or     2-methyl-1,3-thiazol-5-yl, 2-chloropyrimidin-5-yl,     2-trifluoromethylpyrimidin-5-yl, 5,6-difluoropyrid-3-yl,     5-chloro-6-fluoropyrid-3-yl, 5-bromo-6-fluoropyrid-3-yl,     5-iodo-6-fluoropyrid-3-yl, 5-fluoro-6-chloropyrid-3-yl,     5,6-dichloropyrid-3-yl, 5-bromo-6-chloropyrid-3-yl,     5-iodo-6-chloropyrid-3-yl, 5-fluoro-6-bromopyrid-3-yl,     5-chloro-6-bromopyrid-3-yl, 5,6-dibromopyrid-3-yl,     5-fluoro-6-iodopyrid-3-yl, 5-chloro-6-iodopyrid-3-yl,     5-bromo-6-iodopyrid-3-yl, 5-methyl-6-fluoropyrid-3-yl,     5-methyl-6-chloropyrid-3-yl, 5-methyl-6-bromopyrid-3-yl,     5-methyl-6-iodopyrid-3-yl, 5-difluoromethyl-6-fluoropyrid-3-yl,     5-difluoromethyl-6-chloropyrid-3-yl,     5-difluoromethyl-6-bromopyrid-3-yl and     5-difluoromethyl-6-iodopyrid-3-yl. -   A is more preferably selected from the group consisting of     6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid-3-yl,     6-chloro-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl,     2-chloropyrimidin-5-yl, 5-fluoro-6-chloropyrid-3-yl,     5,6-dichloropyrid-3-yl, 5-bromo-6-chloropyrid-3-yl,     5-fluoro-6-bromopyrid-3-yl, 5-chloro-6-bromopyrid-3-yl,     5,6-dibromopyrid-3-yl, 5-methyl-6-chloropyrid-3-yl,     5-chloro-6-iodopyrid-3-yl and 5-difluoromethyl-6-chloropyrid-3-yl. -   A is most preferably selected from the group consisting of     6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl,     2-chloro-1,3-thiazol-5-yl, 5-fluoro-6-chloropyrid-3-yl and     5-fluoro-6-bromopyrid-3-yl.

The term “alkyl”, either alone or in combination with further terms, for example haloalkyl, is understood in the context of the present invention to mean a radical of a saturated, aliphatic hydrocarbon group having 1 to 12 carbon atoms, which may be branched or unbranched. Examples of C₁-C₁₂-alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Among these alkyl radicals, C₁-C₆-alkyl radicals are particularly preferred. C₁-C₄-alkyl radicals are especially preferred.

According to the invention, the term “aryl” is understood to mean an aromatic radical having 6 to 14 carbon atoms, preferably phenyl.

The term “arylalkyl” is understood to mean a combination of “aryl” and “alkyl” radicals defined in accordance with the invention, the radical generally being bonded via the alkyl group; examples thereof are benzyl, phenylethyl or β-methylbenzyl, particular preference being given to benzyl.

In the context of the present invention, halogen-substituted radicals, for example haloalkyl, are understood to mean radicals halogenated once or more than once up to the maximum possible number of substituents. In the case of polyhalogenation, the halogen atoms may be the same or different. Halogen represents fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

The term “alkoxy”, either alone or in combination with further terms, for example haloalkoxy, is understood in the present context to mean an O-alkyl radical, where the term “alkyl” is as defined above.

Optionally substituted radicals may be mono- or polysubstituted, where the substituents may be the same or different in the case of polysubstitution.

The 2,2-difluoroethylimine derivatives of the general formula (IV) can be hydrogenated to the corresponding amines of the general formula (III) with reducing agents known per se to those skilled in the art. For example, it is possible to perform the reduction with

-   -   complex hydrides,     -   non-complex metal or semimetal hydrides,     -   Na/EtOH, or     -   by catalytic hydrogenation.

Complex hydrides are generally understood to mean charged metal complexes which contain at least one hydride ligand. Examples thereof are lithium aluminium hydride (LiAlH₄), LiAlH(O-tert-butyl)₃, LiAlH(O-methyl)₃, NaAlEt₂H₂, sodium borohydride (NaBH₄) and the like. Examples of non-complex metal and semimetal hydrides are AlH₃, DIBAL-H (AlH(isobutyl)₂) and the like. Among these, the use of sodium borohydride (NaBH₄) is particularly preferred. The reaction with the complex metal hydrides or the non-complex metal or semimetal hydrides can be carried out under reduced pressure, at standard pressure or under elevated pressure and at temperatures of −30 to 150° C., preferably −10 to 60° C.

When a catalytic hydrogenation is employed to reduce the compound of the general formula (IV), the catalyst used may be any desired hydrogenation catalyst. Suitable catalysts optionally contain one or more metals of groups 8-10 of the Periodic Table on any desired customary inorganic support. Useful catalysts include, for example, noble metal catalysts, such as ruthenium catalysts, palladium catalysts, platinum catalysts and rhodium catalysts, Raney nickel catalysts and Lindlar catalysts. As well as these heterogeneous catalysts, it is also possible, however, to carrying out hydrogenations over homogeneous catalysts, for example over the Wilkinson catalyst. The corresponding catalysts can also be used in supported form, for example applied to carbon (unactivated or activated carbon), aluminium oxide, silicon dioxide, zirconium dioxide or titanium dioxide. Corresponding catalysts are known per se to those skilled in the art. Raney nickel catalysts are especially preferred.

The catalytic hydrogenation can be carried out under elevated pressure in an autoclave or at standard pressure in a hydrogen gas atmosphere. The hydrogen gas atmosphere may additionally also comprise inert gases, for example argon or nitrogen. The catalytic hydrogenation is preferably carried out at a temperature of 10 to 60° C., more preferably at 20 to 40° C. The hydrogen pressure is typically 0.1 to 50 bar, preferably 0.1 to 30 bar.

Further reagents and hydrogenation conditions used for the hydrogenation of imines are described in the publications of Harada, in Patai, “The chemistry of the Carbon-Nitrogen Double Bond”, pages 276 to 293; and of Rylander, “Catalytic Hydrogenation over Platinum Metals”, pages 291 to 303, Academic Press, New York, 1967.

In general, it is advantageous to perform the process according to the invention for hydrogenation imines in the presence of solvents (diluents). Solvents are advantageously used in such an amount that the reaction mixture remains efficiently stirrable over the entire process of reduction. Useful solvents for performing the process according to the invention include all organic solvents which are inert under the reaction conditions, the type of solvent used depending on the way in which the reduction is performed, i.e. more particularly on the type of reducing agent.

Examples include: halohydrocarbons, especially chlorohydrocarbons, such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, chlorotoluene, trichlorobenzene; alcohols, such as methanol, ethanol, isopropanol, butanol; ethers, such as ethyl propyl ether, methyl tert-butyl ether, methyl n-butyl ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethylglycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichlorodiethyl ether and polyethers of ethylene oxide and/or of propylene oxide; amines such as trimethyl-, triethyl-, tripropyl-, tributylamine, N-methylmorpholine, pyridine, alkylated pyridines and tetramethylenediamine; aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, n-hexane, n-heptane, n-octane, nonane and technical hydrocarbons which may be substituted by fluorine and chlorine atoms, such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; for example so-called white spirits comprising components with boiling points in the range, for example, of 40° C. to 250° C. cymene, petroleum fractions within a boiling range of 70° C. to 190° C., cyclohexane, methylcyclohexane, petroleum ether, ligroin, octane, benzene, toluene, chlorobenzene, bromobenzene, nitrobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, and dimethyl carbonate, dibutyl carbonate or ethylene carbonate; and aliphatic alcohols, such as methanol, ethanol, n-propanol and isopropanol and n-butanol.

Among the aforementioned solvents, alcohols, in particular methanol and ethanol, especially methanol, are preferred.

The amounts of solvent used in the inventive reaction can be varied within a wide range. In general, amounts of solvent in the range of 1 to 50 times the amount of solvent, more preferably of 2 to 40 times the amount of solvent, especially of 2 to 30 times the amount of solvent, based in each case on the 2,2-difluoroethylimine of the general formula (IV) used, are used.

Preference is additionally given especially to the combination of sodium borohydride (NaBH₄) as the hydrogenating agent with alcohols, especially methanol, as the solvent.

The inventive reaction can be carried out with this system composed of sodium borohydride (NaBH₄) and methanol especially as follows: the imine is initially charged in the alcohol and the sodium borohydride is added in portions with cooling. Subsequently, the mixture is stirred at a temperature of 30 to 50° C. and then about 1 to 3 equivalents of water are added, based on the amount of alcohol. This is followed by extraction with an organic solvent in a customary manner.

The hydrogenation is generally effected under those reaction conditions (pressure, temperature, stoichiometry etc.), under which the imine group is hydrogenated to a saturated group, but the other functional groups present in the molecule simultaneously remain unchanged.

The workup (purification) and isolation of the hydrogenated imines can be effected, for example, by crystallization and/or distillation.

The present invention additionally also relates to the use of the compounds of the general formula (IV) to prepare compounds of the general formula (III), as disclosed in the process described above.

The compounds of the general formula (IV) required for the inventive reaction can be obtained by reacting aldehydes of the general formula (VI)

in which A is as defined above with 2,2-difluoroethylamine to give a compound of the general formula (IV)

with condensation.

The 2,2-difluoroethylamine required for this reaction is commercially available and can be prepared by literature methods (J. Medicinal Chemistry (1989), 32(5), 957-961).

The aldehydes of the formula (II) are commercially available or can be prepared by literature methods (cf., for example, 6-methylnicotinaldehyde: EP 0 104 876 A2; 2-chloro-pyrazine-5-carboxaldehyde: DE 3314196 A1).

It is optionally possible to add an acid as a catalyst to the reaction to obtain the compounds of the general formula (IV). Examples thereof are acetic acid, p-toluenesulphonic acid, trifluoroacetic acid. Preference is given to using acetic acid.

When catalysts of this kind are used, the amount thereof may be 0.01 to 10 percent by weight, based on the 2,2-difluoroethylamine used.

In a preferred embodiment of the present invention, the 2,2-difluoroethylamine is used in the form of a salt. This allows the addition of Lewis acid to be dispensed with or reduced. Useful salts include, for example, the hydrochloride, the acetate or the sulphate.

The reaction to prepare the compounds of the general formula (IV) can additionally also be carried out in such a way that the water formed in the reaction between amine and aldehyde is removed from the reaction mixture by condensation. This is possible, for example, through use of water-binding agents, for example sodium sulphate, magnesium sulphate or molecular sieve, or through use of an apparatus for water separation.

The reaction to prepare the compounds of the general formula (IV) can generally be carried out under reduced pressure, at standard pressure or under elevated pressure. The temperatures employed can likewise vary depending on the substrates used, and are easy for the person skilled in the art to determine by routine tests. For example, the reaction to prepare the compounds of the general formula (IV) can be carried out at a temperature of −20 to 200° C., preferably 10 to 100° C. Particular preference is given to performing the reaction at standard pressure and temperatures of 10 to 100° C.

The reaction to prepare the imines of the general formula (IV) can additionally also be carried out in the presence of solvents (diluents). In this process step too, the solvents are preferably used in such an amount that the reaction mixture remains efficiently stirrable over the entire process of the reduction. Useful solvents for performing the process according to the invention for preparing the 2,2-difluoroethylimine derivatives of the general formula (IV) include all organic solvents which are inert under the reaction conditions.

Examples include: halohydrocarbons, especially chlorohydrocarbons, such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, chlorotoluene, trichlorobenzene; alcohols, such as methanol, ethanol, isopropanol, butanol; ethers, such as ethyl propyl ether, methyl tert-butyl ether, methyl n-butyl ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethylglycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, dichlorodiethyl ether and polyethers of ethylene oxide and/or of propylene oxide; nitrohydrocarbons such as nitromethane, nitroethane, nitropropane, nitrobenzene, chloronitrobenzene, o-nitrotoluene; nitriles such as acetonitrile, methyl nitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile, phenyl nitrile, m-chlorobenzonitrile, and compounds such as tetrahydrothiophene dioxide and dimethyl sulphoxide, tetramethylene sulphoxide, dipropyl sulphoxide, benzyl methyl sulphoxide, diisobutyl sulphoxide, dibutyl sulphoxide, diisoamyl sulphoxide; sulphones such as dimethyl sulphone, diethyl sulphone, dipropyl sulphone, dibutyl sulphone, diphenyl sulphone, dihexyl sulphone, methyl ethyl sulphone, ethyl propyl sulphone, ethyl isobutyl sulphone and pentamethylene sulphone; aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane and technical hydrocarbons which may be substituted by fluorine and chlorine atoms, such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; for example so-called white spirits comprising components with boiling points in the range, for example, of 40° C. to 250° C., cymene, petroleum fractions within a boiling range of 70° C. to 190° C., cyclohexane, methylcyclohexane, petroleum ether, ligroin, octane, benzene, toluene, chlorobenzene, bromobenzene, nitrobenzene and xylene. Among the aforementioned solvents, xylene, chlorobenzene, cyclohexane and toluene are especially preferred.

In a further embodiment, the reaction between amine and aldehyde can also be effected in substance.

If the reaction is carried out in a solvent, the solvent can be removed by distillation after the end of the reaction. This can be done under standard pressure or reduced pressure, at room temperature or elevated temperatures. The mixture can also be transferred directly into the hydrogenation, which is advantageous especially owing to economic considerations. In this embodiment of the process according to the invention, a workup of the 2,2-difluoroethylimine derivative is then dispensed with.

The present invention further additionally provides compounds of the general formula (IV), which are used as intermediates in the preparation of the target compounds of the general formula (III):

In these intermediates, the substituent A is generally defined as follows:

-   -   pyrid-2-yl or pyrid-4-yl, or pyrid-3-yl which is optionally         6-substituted by fluorine, chlorine, bromine, methyl,         trifluoromethyl or trifluoromethoxy, or pyridazin-3-yl which is         optionally 6-substituted by chlorine or methyl, or pyrazin-3-yl,         or 2-chloropyrazin-5-yl, or 1,3-thiazol-5-yl which is optionally         2-substituted by chlorine or methyl, or     -   pyrimidinyl, pyrazolyl, thiophenyl, oxazolyl, isoxazolyl,         1,2,4-oxadiazolyl, isothiazolyl, 1,2,4-triazolyl or         1,2,5-thiadiazolyl, which is optionally substituted by fluorine,         chlorine, bromine, cyano, nitro, C₁-C₄-alkyl (which is         optionally substituted by fluorine and/or chlorine),         C₁-C₃-alkylthio (which is optionally substituted by fluorine         and/or chlorine), or C₁-C₃-alkylsulphonyl (which is optionally         substituted by fluorine and/or chlorine), or

-   -   in which     -   X is halogen, alkyl or haloalkyl and     -   Y is halogen, alkyl, haloalkyl, haloalkoxy, azido or cyano.

Preferred, particularly preferred and very particularly preferred substituents or ranges of the A radical shown in the abovementioned general formulae (III) and (IV) are elucidated below.

-   A is preferably selected from the group consisting of     6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid-3-yl,     6-methylpyrid-3-yl, 6-trifluoromethylpyrid-3-yl,     6-trifluoromethoxypyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl,     6-methyl-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl or     2-methyl-1,3-thiazol-5-yl, 2-chloropyrimidin-5-yl,     2-trifluoromethylpyrimidin-5-yl, 5,6-difluoropyrid-3-yl,     5-chloro-6-fluoropyrid-3-yl, 5-bromo-6-fluoropyrid-3-yl,     5-iodo-6-fluoropyrid-3-yl, 5-fluoro-6-chloropyrid-3-yl,     5,6-dichloropyrid-3-yl, 5-bromo-6-chloropyrid-3-yl,     5-iodo-6-chloropyrid-3-yl, 5-fluoro-6-bromopyrid-3-yl,     5-chloro-6-bromopyrid-3-yl, 5,6-dibromopyrid-3-yl,     5-fluoro-6-iodopyrid-3-yl, 5-chloro-6-iodopyrid-3-yl,     5-bromo-6-iodopyrid-3-yl, 5-methyl-6-fluoropyrid-3-yl,     5-methyl-6-chloropyrid-3-yl, 5-methyl-6-bromopyrid-3-yl,     5-methyl-6-iodopyrid-3-yl, 5-difluoromethyl-6-fluoropyrid-3-yl,     5-difluoromethyl-6-chloropyrid-3-yl,     5-difluoromethyl-6-bromopyrid-3-yl and     5-difluoromethyl-6-iodopyrid-3-yl. -   A is more preferably selected from the group consisting of     6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid-3-yl,     6-chloro-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl,     2-chloropyrimidin-5-yl, 5-fluoro-6-chloropyrid-3-yl,     5,6-dichloropyrid-3-yl, 5-bromo-6-chloropyrid-3-yl,     5-fluoro-6-bromopyrid-3-yl, 5-chloro-6-bromopyrid-3-yl,     5,6-dibromopyrid-3-yl, 5-methyl-6-chloropyrid-3-yl,     5-chloro-6-iodopyrid-3-yl and 5-difluoromethyl-6-chloropyrid-3-yl. -   A is most preferably selected from the group consisting of     6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl,     2-chloro-1,3-thiazol-5-yl, 5-fluoro-6-chloropyrid-3-yl and     5-fluoro-6-bromopyrid-3-yl.

The compounds of the general formula (IV) can be used as reactants to prepare 2,2-difluoroethylamine derivatives of the general formula (III).

Proceeding from the compounds of the general formula (III) which are obtained by the process according to the invention, it is possible to prepare insecticidally active enaminocarbonyl compounds which include 2,2-difluoroethylamino units and are described, for example, in international patent applications WO 2007/115644 and WO 2007/115646.

For this purpose, the compounds of the general formula (III)

can be alkenylated on the secondary amine nitrogen, for example by reaction with tetronic acid or derivatives thereof. A corresponding reaction is described in detail in scheme I of DE 10 2006 015 467 and leads directly to the insecticidally active enaminocarbonyl compounds.

The present invention is illustrated in detail by the examples which follow, though the examples should not be interpreted in such a manner as to limit the invention.

PREPARATION EXAMPLES Example 1

To a solution of 74.34 g of 6-chloropyridine-3-carbaldehyde in 46 g of toluene are added 41.8 g of 2,2-difluoroethylamine at room temperature. The reaction mixture is stirred at room temperature for 2 hours. Subsequently, 120 g of anhydrous magnesium sulphate are added and the mixture is stirred at 50° C. for a further 5 hours. The reaction mixture is cooled to room temperature and filtered, and the filter residue is washed with toluene. The solvent is removed under reduced pressure and 100.2 g of N-[(6-chloropyridin-3-yl)methylidene)]-2,2-difluoroethylamine are obtained in a purity of 95.5% (this corresponds to 94% yield).

¹H NMR (CDCl₃, 298K) δ: 4.05 m (2H), 6.5 t (1H, CHF₂), 7.63 d (1H), 8.20 d (1H), 8.56 s (1H), 8.75 d (1H)

Example 2

To a solution of 74 g of N-[(6-chloropyridin-3-yl)methylidene)]-2,2-difluoroethylamine (from Example 1) in 343 g of ethanol are added 5 g of Raney nickel catalyst, and hydrogenation is effected with 20 bar of hydrogen at room temperature for 24 h. The catalyst is filtered off, the residue is washed with 100 ml of ethanol and the solvent is removed under reduced pressure. This gives 71.4 g of N-[(6-chloropyridin-3-yl)methyl)]-2,2-difluoroethylamine in a purity of 95% (this corresponds to 94% yield).

NMR (d-DMSO): 1H (s, 8.35 ppm); 1H (dd, 7.8 ppm); 1H (d, 7.46 ppm); 1H (tt, 6.02 ppm); 2H (s, 3.8 ppm); 2H (td, 2.9 ppm)

Example 3

To a solution of 5 g of N-[(6-chloropyridin-3-yl)methylidene)]-2,2-difluoroethylamine in 23 of ethanol are added 1.1 g of sodium borohydride in portions, and the mixture is stirred at room temperature. Subsequently, the mixture is heated briefly to 50° C. and then poured onto 100 ml of water. The mixture is extracted twice with 100 ml each time of methylene chloride and the combined organic phases are concentrated under reduced pressure. This gives 4.5 g of N-[(6-chloropyridin-3-yl)methyl)]-2,2-difluoroethylamine in a purity of 93% (this corresponds to 86% yield).

NMR data: see Example 2 

1. A process for preparing a 2,2-difluoroethylamine compound, comprising hydrogenating a 2,2-difluoroethylimine compound of formula (IV) to a corresponding 2,2-difluoroethylamine compound of formula (III):

where the A radical is defined as follows: pyrid-2-yl or pyrid-4-yl, or pyrid-3-yl which is optionally 6-substituted by fluorine, chlorine, bromine, methyl, trifluoromethyl or trifluoromethoxy, or pyridazin-3-yl which is optionally 6-substituted by chlorine or methyl, or pyrazin-3-yl, or 2-chloropyrazin-5-yl, or 1,3-thiazol-5-yl which is optionally 2-substituted by chlorine or methyl, or pyrimidinyl, pyrazolyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, isothiazolyl, 1,2,4-triazolyl or 1,2,5-thiadiazolyl, which is optionally substituted by fluorine, chlorine, bromine, cyano, nitro, C₁-C₄-alkyl (which is optionally substituted by fluorine and/or chlorine), C₁-C₃-alkylthio (which is optionally substituted by fluorine and/or chlorine), or C₁-C₃-alkylsulphonyl (which is optionally substituted by fluorine and/or chlorine), or

in which X is halogen, alkyl or haloalkyl and Y is halogen, alkyl, haloalkyl, haloalkoxy, azido or cyano.
 2. A process according to claim 1, wherein the hydrogenation is carried out with complex hydrides, non-complex metal and/or semimetal hydrides, Na/EtOH and/or by catalytic hydrogenation.
 3. A process for preparing a compound of formula (IV)

wherein a compound of the aldehydes of formula (VI)

is reacted with 2,2-difluoroethylamine where the A radical is defined as follows: pyrid-2-yl or pyrid-4-yl, or pyrid-3-yl which is optionally 6-substituted by fluorine, chlorine, bromine, methyl, trifluoromethyl or trifluoromethoxy, or pyridazin-3-yl which is optionally 6-substituted by chlorine or methyl, or pyrazin-3-yl, or 2-chloropyrazin-5-yl, or 1,3-thiazol-5-yl which is optionally 2-substituted by chlorine or methyl, or pyrimidinyl, pyrazolyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, isothiazolyl, 1,2,4-triazolyl or 1,2,5-thiadiazolyl, which is optionally substituted by fluorine, chlorine, bromine, cyano, nitro, C₁-C₄-alkyl (which is optionally substituted by fluorine and/or chlorine), C₁-C₃-alkylthio (which is optionally substituted by fluorine and/or chlorine), or C₁-C₃-alkylsulphonyl (which is optionally substituted by fluorine and/or chlorine), or

in which X is halogen, alkyl or haloalkyl and Y is halogen, alkyl, haloalkyl, haloalkoxy, azido or cyano.
 4. A process according to claim 3, further comprising hydrogenating the 2,2-difluoroethylimine compound of formula (IV) to a corresponding 2,2-difluoroethylamine compound of formula (III):

where the A radical is defined as follows: pyrid-2-yl or pyrid-4-yl, or pyrid-3-yl which is optionally 6-substituted by fluorine, chlorine, bromine, methyl, trifluoromethyl or trifluoromethoxy, or pyridazin-3-yl which is optionally 6-substituted by chlorine or methyl, or pyrazin-3-yl, or 2-chloropyrazin-5-yl, or 1,3-thiazol-5-yl which is optionally 2-substituted by chlorine or methyl, or pyrimidinyl, pyrazolyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, isothiazolyl, 1,2,4-triazolyl or 1,2,5-thiadiazolyl, which is optionally substituted by fluorine, chlorine, bromine, cyano, nitro, C₁-C₄-alkyl (which is optionally substituted by fluorine and/or chlorine), C₁-C₃-alkylthio (which is optionally substituted by fluorine and/or chlorine), or C₁-C₃-alkylsulphonyl (which is optionally substituted by fluorine and/or chlorine), or

in which X is halogen, alkyl or haloalkyl and Y is halogen, alkyl, haloalkyl, haloalkoxy, azido or cyano.
 5. A process according to claim 1, wherein the A radical is: 6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-methylpyrid-3-yl, 6-trifluoromethylpyrid-3-yl, 6-trifluoromethoxypyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl, 6-methyl-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl or 2-methyl-1,3-thiazol-5-yl, 2-chloropyrimidin-5-yl, 2-trifluoromethylpyrimidin-5-yl, 5,6-difluoropyrid-3-yl, 5-chloro-6-fluoropyrid-3-yl, 5-bromo-6-fluoropyrid-3-yl, 5-iodo-6-fluoropyrid-3-yl, 5-fluoro-6-chloropyrid-3-yl, 5,6-dichloropyrid-3-yl, 5-bromo-6-chloropyrid-3-yl, 5-iodo-6-chloropyrid-3-yl, 5-fluoro-6-bromopyrid-3-yl, 5-chloro-6-bromopyrid-3-yl, 5,6-dibromopyrid-3-yl, 5-fluoro-6-iodopyrid-3-yl, 5-chloro-6-iodopyrid-3-yl, 5-bromo-6-iodopyrid-3-yl, 5-methyl-6-fluoropyrid-3-yl, 5-methyl-6-chloropyrid-3-yl, 5-methyl-6-bromopyrid-3-yl, 5-methyl-6-iodopyrid-3-yl, 5-difluoromethyl-6-fluoropyrid-3-yl, 5-difluoromethyl-6-chloropyrid-3-yl, 5-difluoromethyl-6-bromopyrid-3-yl, or 5-difluoro-methyl-6-iodopyrid-3-yl.
 6. A process according to claim 1, wherein the A radical is: 6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl, 2-chloropyrimidin-5-yl, 5-fluoro-6-chloropyrid-3-yl, 5,6-dichloropyrid-3-yl, 5-bromo-6-chloropyrid-3-yl, 5-fluoro-6-bromopyrid-3-yl, 5-chloro-6-bromopyrid-3-yl, 5,6-dibromopyrid-3-yl, 5-methyl-6-chloropyrid-3-yl, 5-chloro-6-iodo-pyrid-3-yl, or 5-difluoromethyl-6-chloropyrid-3-yl.
 7. A process according to claim 1, wherein the A radical is: 6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl, 5-fluoro-6-chloropyrid-3-yl, or 5-fluoro-6-bromopyrid-3-yl.
 8. A process according to claim 1, wherein the A radical is 6-chloropyrid-3-yl.
 9. A process according to claim 3, wherein the A radical is: 6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-methylpyrid-3-yl, 6-trifluoromethylpyrid-3-yl, 6-trifluoromethoxypyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl, 6-methyl-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl or 2-methyl-1,3-thiazol-5-yl, 2-chloropyrimidin-5-yl, 2-trifluoromethylpyrimidin-5-yl, 5,6-difluoropyrid-3-yl, 5-chloro-6-fluoropyrid-3-yl, 5-bromo-6-fluoropyrid-3-yl, 5-iodo-6-fluoropyrid-3-yl, 5-fluoro-6-chloropyrid-3-yl, 5,6-dichloropyrid-3-yl, 5-bromo-6-chloropyrid-3-yl, 5-iodo-6-chloropyrid-3-yl, 5-fluoro-6-bromopyrid-3-yl, 5-chloro-6-bromopyrid-3-yl, 5,6-dibromopyrid-3-yl, 5-fluoro-6-iodopyrid-3-yl, 5-chloro-6-iodopyrid-3-yl, 5-bromo-6-iodopyrid-3-yl, 5-methyl-6-fluoropyrid-3-yl, 5-methyl-6-chloropyrid-3-yl, 5-methyl-6-bromopyrid-3-yl, 5-methyl-6-iodopyrid-3-yl, 5-difluoromethyl-6-fluoropyrid-3-yl, 5-difluoromethyl-6-chloropyrid-3-yl, 5-difluoromethyl-6-bromopyrid-3-yl, or 5-difluoro-methyl-6-iodopyrid-3-yl.
 10. A process according to claim 3, wherein the A radical is: 6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl, 2-chloropyrimidin-5-yl, 5-fluoro-6-chloropyrid-3-yl, 5,6-dichloropyrid-3-yl, 5-bromo-6-chloropyrid-3-yl, 5-fluoro-6-bromopyrid-3-yl, 5-chloro-6-bromopyrid-3-yl, 5,6-dibromopyrid-3-yl, 5-methyl-6-chloropyrid-3-yl, 5-chloro-6-iodo-pyrid-3-yl, or 5-difluoromethyl-6-chloropyrid-3-yl.
 11. A process according to claim 3, wherein the A radical is: 6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl, 5-fluoro-6-chloropyrid-3-yl, or 5-fluoro-6-bromopyrid-3-yl.
 12. A process according to claim 3, wherein the A radical is 6-chloropyrid-3-yl.
 13. A compound of formula (IV)

in which the A radical is defined as follows: pyrid-2-yl or pyrid-4-yl, or pyrid-3-yl which is optionally 6-substituted by fluorine, chlorine, bromine, methyl, trifluoromethyl or trifluoromethoxy, or pyridazin-3-yl which is optionally 6-substituted by chlorine or methyl, or pyrazin-3-yl, or 2-chloropyrazin-5-yl, or 1,3-thiazol-5-yl which is optionally 2-substituted by chlorine or methyl, or pyrimidinyl, pyrazolyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, isothiazolyl, 1,2,4-triazolyl or 1,2,5-thiadiazolyl, which is optionally substituted by fluorine, chlorine, bromine, cyano, nitro, C₁-C₄-alkyl (which is optionally substituted by fluorine and/or chlorine), C₁-C₃-alkylthio (which is optionally substituted by fluorine and/or chlorine), or C₁-C₃-alkylsulphonyl (which is optionally substituted by fluorine and/or chlorine), or

in which X is halogen, alkyl or haloalkyl and Y is halogen, alkyl, haloalkyl, haloalkoxy, azido or cyano.
 14. A compound according to claim 13, wherein the A radical is: 6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-methylpyrid-3-yl, 6-trifluoromethylpyrid-3-yl, 6-trifluoromethoxypyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl, 6-methyl-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl or 2-methyl-1,3-thiazol-5-yl, 2-chloropyrimidin-5-yl, 2-trifluoromethylpyrimidin-5-yl, 5,6-difluoropyrid-3-yl, 5-chloro-6-fluoropyrid-3-yl, 5-bromo-6-fluoropyrid-3-yl, 5-iodo-6-fluoropyrid-3-yl, 5-fluoro-6-chloropyrid-3-yl, 5,6-dichloropyrid-3-yl, 5-bromo-6-chloropyrid-3-yl, 5-iodo-6-chloropyrid-3-yl, 5-fluoro-6-bromopyrid-3-yl, 5-chloro-6-bromopyrid-3-yl, 5,6-dibromopyrid-3-yl, 5-fluoro-6-iodopyrid-3-yl, 5-chloro-6-iodopyrid-3-yl, 5-bromo-6-iodopyrid-3-yl, 5-methyl-6-fluoropyrid-3-yl, 5-methyl-6-chloropyrid-3-yl, 5-methyl-6-bromopyrid-3-yl, 5-methyl-6-iodopyrid-3-yl, 5-difluoromethyl-6-fluoropyrid-3-yl, 5-difluoromethyl-6-chloropyrid-3-yl, 5-difluoromethyl-6-bromopyrid-3-yl, or 5-difluoro-methyl-6-iodopyrid-3-yl.
 15. A compound according to claim 13, wherein the A radical is: 6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl, 2-chloropyrimidin-5-yl, 5-fluoro-6-chloropyrid-3-yl, 5,6-dichloropyrid-3-yl, 5-bromo-6-chloropyrid-3-yl, 5-fluoro-6-bromopyrid-3-yl, 5-chloro-6-bromopyrid-3-yl, 5,6-dibromopyrid-3-yl, 5-methyl-6-chloropyrid-3-yl, 5-chloro-6-iodo-pyrid-3-yl, or 5-difluoromethyl-6-chloropyrid-3-yl.
 16. A compound according to claim 13, wherein the A radical is: 6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-chloro-1,4-pyridazin-3-yl, 2-chloro-1,3-thiazol-5-yl, 5-fluoro-6-chloropyrid-3-yl, or 5-fluoro-6-bromopyrid-3-yl.
 17. A compound according to claim 13, wherein the A radical is 6-chloropyrid-3-yl. 